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Abstract

Gliomas, a prevalent form of malignant brain tumors in adults, often exhibit mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Temozolomide (TMZ) is a commonly used chemotherapy drug for treating gliomas; however, the development of drug resistance poses a significant challenge to its effectiveness.

My study aimed to investigate new drug options for IDH1 mutant gliomas and was divided into two main parts. The first part focused on reversing TMZ resistance and identifying synergistic drugs, while the second part sought alternative treatments for IDH1 mutant TMZ-resistant gliomas.

To achieve the objectives of the first part, patient-derived glioma tumorspheres (PDTs) harboring IDH1 mutations were utilized. Vehicle and TMZ treated tumor models were subjected to transcriptional, metabolic, and epigenetic analyses. Transcriptome analysis revealed the upregulation of the p53 signaling pathway and its associated transcription factor, TP53. Notably, combining the p53 activator RITA with TMZ demonstrated strong synergy in certain PDTs. Metabolome analysis uncovered that glycolytic inhibition with the glucose analog 2-DG (2-Deoxy-D-glucose) or combining Mildronate, L-carnitine biosynthesis inhibitor, with TMZ treatment showed efficacy in specific PDTs. Additionally, employing epigenetic approaches using decitabine (DAC) in combination with TMZ revealed robust synergistic effects in select PDTs. These findings underscore the significance of genetic and metabolic heterogeneity among cells in gliomas.

In the pursuit of alternative drugs, a high-throughput miniaturized screening identified more than 20 potential candidate drugs, among which the YAP inhibitor Verteporfin (VP) emerged as a promising option. VP exhibited anti-tumor activity in IDH1 mutant PDTs independent of the YAP1 protein. It downregulated the nucleocytoplasmic transport pathway, with NUP107 identified as an upstream regulator associated with VP response.

In conclusion, this study elucidated the intricate interplay of signaling pathways and their impact on drug sensitivity in diverse glioma cell populations. It emphasized the need to consider the complexities inherent to gliomas when devising effective therapeutic strategies. The findings provide valuable insights into the development of alternative treatments and strategies to overcome TMZ resistance in IDH1 mutant gliomas.